Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial
Authors: Pauline Amuge, Abbas Lugemwa, Ben Wynne, Hilda A Mujuru, Avy Violari, Cissy M Kityo, Moherndran Archary, Ebrahim Variava, Ellen White, Rebecca M Turner, Clare Shakeshaft, Shabinah Ali, Kusum J Nathoo, Lorna Atwine, Afaaf Liberty, Dickson Bbuye, Elizabeth Kaudha, Rosie Mngqibisa, Modehei Mosala, Vivian Mumbiro, Annet Nanduudu, Rogers Ankunda, Lindiwe Maseko, Adeodata R Kekitiinwa, Carlo Giaquinto, Pablo Rojo, Diana M Gibb, Anna Turkova, Deborah Ford, Amina Farhana Mehar (nee Abdulla), Pattamukkil Abraham, Elaine Abrams, Judith Acero, Gerald Muzorah Agaba, Grace Ahimbisibwe, Barbara Ainebyoona, Winnie Akobye, Yasmeen Akhalwaya, Nazim Akoojee, Shabinah S. Ali, Pauline Amuge, Catherine Andrea, Maria Angeles Muñoz Fernandez, Rogers Ankunda, Diana Antonia Rutebarika, Suvaporn Anugulruengkitt, Tsitsi Apollo, Moherndran Archary, Ronelle Arendze, Juliet Ategeka, Eunice Atim, Lorna Atwine, Abdel Babiker, Sarah Babirye, Enock Babu, Edward Bagirigomwa, Angella Baita, David Balamusani, Patsy Baliram, David Baliruno, Colin Ball, Henry Balwa, Alasdair Bamford, Srini Bandi, Dominique Barker, Linda Barlow-Mosha, Dickson Bbuye, Shazia Begum, Osee Behuhuma, Sarah Bernays, Rogers Besigye, Maria Bester, Joyline Bhiri, Davide Bilardi, Kristien Bird, Pauline Bollen, Chiara Borg, Anne-Marie Borges Da Silva, Jackie Brown, Elena Bruno, Torsak Bunupuradah, David Burger, Nomzamo Buthelezi, Mutsa Bwakura-Dangarembizi, Africanus Byaruhanga, Joanna Calvert, Petronelle Casey, Haseena Cassim, Sphiwee Cebekhulu, Sanuphong Chailert, Suwalai Chalermpantmetagul, Wanna Chamjamrat, Man Chan, Precious Chandiwana, Thannapat Chankun, Sararut Chanthaburanun, Nuttawut Chanto, Ennie Chidziva, Minenhle Chikowore, Joy Chimanzi, Dujrudee Chinwong, Stuart Chitongo, Moses Chitsamatanga, Joshua Choga, Duangrat Chutima, Polly Clayden, Alexandra Coelho, Angela Colbers, Alexandra Compagnucci, Ana Constança Mendes, Magda Conway, Mark F. Cotton, Jane Crawley, Tim R. Cressey, Jacky Crisp, Ana Cristina Matos, Sumaya Dadan, Jacqui Daglish, Siva Danaviah, Tseleng Daniel, Anita De Rossi, Sukanda Denjanta, Els Dobbels, Maria Dowie, Prosper Dube, Benedictor Dube, Nimisha Dudakia, Alice Elwana, Cristina Epalza, David Eram, Juan Erasmus, Peter Erim, Luis Escosa Garcia, Zaakirah Essack, Carolina Estepa, Monica Etima, Alexandre Fernandes, Maite Fernandez, Felicity Fitzgerald, Jacquie Flynn, Deborah Ford, Claudia Fortuny Guasch, Caroline Foster, George Fourie, Yolandie Fourie, Sophie Foxall, Derusha Frank, Kate Gandhi, India Garcia, Kathleen Gartner, Joshua Gasa, Gugu Gasa, Carlo Giaquinto, Diana M. Gibb, Coral Gomez Rico, Daniel Gomez-Pena, Secrecy Gondo, Anna Goodman, Maria Gorreti Nakalema, Winnie Gozhora, Pisut Greetanukroh, Biobanco Gregorio Maranon, Tiziana Grossele, Shamiso Gwande, Tapiwa Gwaze, Tsitsi Gwenzi, James Hakim, Emmanuel Hakiza, Abdul Hamid Kaka, Ashley Harley, Mornay Isaacs, Richard Isabirye, Wilber Ishemunyoro, Tom Jacobs, Lungile Jafta, Nasir Jamil, Anita Janse Janse van Rensburg, Vinesh Jeaven, Maria José Mellado Peña, Gonzague Jourdain, Katabalwa Juliet, Thidarat Jumpimai, Raungwit Junkaew, Thidarat Jupimai, Winfred Kaahwa, Mildred Kabasonga, Olivia Kaboggoza, Rose Jacqueline Kadhuba, Ampika Kaewbundit, Kanyanee Kaewmamueng, Bosco Kafufu, Brenda Kakayi, Phakamas Kamboua, Suparat Kanjanavanit, Gladys Kasangaki, Naruporn Kasipong, Miriam Kasozi, Hajira Kataike, Chrispus Katemba, Elizabeth Kaudha, Nkata Kekane, Adeodata R. Kekitiinwa, Edridah Keminyeto, Woottichai Khamduang, Warunee Khamjakkaew, Jiraporn Khamkon, Sasipass Khannak, Orapin Khatngam, Tassawan Khayanchoomnoom, Busi Khumalo, Mirriam Khunene, Suwimon Khusuwan, Phionah Kibalama, Robinah Kibenge, Anthony Kirabira, Cissy M. Kityo, Lameck Kiyimba, Nigel Klein, Soraya Klinprung, Robin Kobbe, Olivia Kobusingye, Josephine Kobusungye, Areerat Kongponoi, Christoph Königs, Olivier Koole, Christelle Kouakam, Nitinart Krueduangkam, Namthip Kruenual, Nuananong Kunjaroenrut, Raymonds Kyambadde, Priscilla Kyobutungi, Flavia Kyomuhendo, Erinah Kyomukama, Reshma Lakha, Cleopatra Langa, Laddawan Laomanit, Emily Lebotsa, Prattana Leenasirimakul, Lawrence Lekku, Sarah Lensen, Valériane Leroy, Jin Li, Afaaf Liberty, Juthamas Limplertjareanwanich, Emma Little, Abbas Lugemwa, Ezra Lutalo, Jose Luis Jimenez, Hermione Lyall, Candice MacDonald, Gladness Machache, Penelope Madlala, Tryphina Madonsela, Nomfundo Maduna, Joel Maena, Apicha Mahanontharit, Collin Makanga, Candice Makola, Shafic Makumbi, Lucille Malgraaf, Angelous Mamiane, Felicia Mantkowski, Wendy Mapfumo, Laura Marques, Agnes Mary Mugagga, Lindiwe Maseko, Tshepiso Masienyane, Ruth Mathiba, Farai Matimba, Sajeeda Mawlana, Emmanuel Mayanja, Fatima Mayat, Ritah Mbabazi, Nokuthula Mbadaliga, Faith Mbasani, Kathleen McClaughlin, Helen McIlleron, Watchara Meethaisong, Patricia Mendez Garcia, Annet Miwanda, Carlota Miranda, Siphiwe Mkhize, Kgosimang Mmolawa, Rosie Mngqibisa, Fatima Mohamed, Tumelo Moloantoa, Maletsatsi Monametsi, Samuel Montero, Cecilia L. Moore, Rejoice Mosia, Columbus Moyo, Mumsy Mthethwa, Shepherd Mudzingwa, Tawona Mudzviti, Hilda Mujuru, Emmanuel Mujyambere, Trust Mukanganiki, Cynthia Mukisa Williams, Mark Mulder, Disan Mulima, Alice Mulindwa, Vivian Mumbiro, Zivai Mupambireyi, Alba Murciano Cabeza, Herbert Murungi, Dorothy Murungu, Sandra Musarurwa, Victor Musiime, Alex V. Musiime, Maria Musisi, Philippa Musoke, Barbara Musoke Nakirya, Godfrey Musoro, Sharif Musumba, Sobia Mustafa, Shirley Mutsai, Phyllis Mwesigwa Rubondo, Mariam Naabalamba, Immaculate Nagawa, Allemah Naidoo, Shamim Nakabuye, Sarah Nakabuye, Sarah Nakalanzi, Justine Nalubwama, Annet Nalugo, Stella Nalusiba, Clementine Namajja, Sylvia Namanda, Paula Namayanja, Esther Nambi, Rachael Kikabi Namuddu, Stella Namukwaya, Florence Namuli, Josephine Namusanje, Rosemary Namwanje, Anusha Nanan-kanjee, Annet Nanduudu, Charity Nankunda, Joanita Nankya Baddokwaya, Maria Nannungi, Winnie Nansamba, Kesdao Nanthapisal, Juliet Nanyonjo, Sathaporn Na-Rajsima, Claire Nasaazi, Helena Nascimento, Eleni Nastouli, Wipaporn Natalie Songtaweesin, Kusum Nathoo, Ian Natuhurira, Rashidah Nazzinda, Thabisa Ncgaba, Milly Ndigendawani, Makhosonke Ndlovu, Georgina Nentsa, Chaiwat Ngampiyaskul, Ntombenhle Ngcobo, Nicole Ngo Giang Huong, Pia Ngwaru, Ruth Nhema, Emily Ninsiima, Gloria Ninsiima, Misheck Nkalo Phiri, Antoni Noguera Julian, Monica Nolan, Thornthun Noppakaorattanamanee, Muzamil Nsibuka Kisekka, Eniola Nsirim, Rashina Nundlal, Rosita Nunes, Lungile Nyantsa, Mandisa Nyati, Sean O'Riordan, Paul Ocitti Labeja, Denis Odoch, Rachel Oguntimehin, Martin Ojok, Geoffrey Onen, Wilma Orange, Pradthana Ounchanum, Benson Ouma, Andreia Padrao, Deborah Pako, Anna Parker, Malgorzata Pasko-Szcech, Reena Patel, Rukchanok Peongjakta, Turian Petpranee, Tasmin Phillips, Jackie Philps, Laura Picault, Sonja Pieterse, Helena Pinheiro, Supawadee Pongprapass, Anton Pozniak, Andrew Prendergast, Luis Prieto Tato, Patcharee Puangmalai, Thanyawee Puthanakit, Modiehi Rakgokong, Helena Ramos, Nastassja Ramsagar, Cornelius Rau, Yoann Riault, Pablo Rojo Conejo, Basiimwa Roy Clark, Eddie Rubanga, Baker Rubinga, Chutima Ruklao, Pattira Runarassamee, Diana Antonia Rutebarika, Chalermpong Saenjum, Chayakorn Saewtrakool, Yacine Saidi, Talia Sainz Costa, Chutima Saisaengjan, Rebecca Sakwa, Tatiana Sarfati, Noshalaza Sbisi, Dihedile Scheppers, Stephan Schultze-Strasser, Ulf Schulze-Sturm, Karen Scott, Janet Seeley, Robert Serunjogi, Leora Sewnarain, Clare Shakeshaft, Subashinie Sidhoo, Mercy Shibemba, Delane Shingadia, Sheleika Singh, Wasna Sirirungsi, Sibongile Sithebe, Theresa Smit, Kurt Smith, Marlize Smuts, Moira Spyer, Worathip Sripaoraya, Ussanee Srirompotong, Warunee Srisuk, Mark Ssenyonga, Patamawadee Sudsaard, Praornsuda Sukrakanchana, Pathanee Tearsansern, Carla Teixeira, Kanchana Than-in-at, Thitiwat Thapwai, Yupawan Thaweesombat, Jutarat Thewsoongnoen, Rodolphe Thiébaut, Margaret Thomason, Laura Thrasyvoulou, Khanungnit Thungkham, Judith Tikabibamu, Gloria Tinago, Ketmookda Trairat, Gareth Tudor-Williams, Mercy Tukamushaba, Deogratiuos Tukwasibwe, Julius Tumusiime, Joana Tuna, Anna Turkova, Rebecca Turner, Arttasid Udomvised, Aasia Vadee, Hesti Van Huyssteen, Nadine Van Looy, Ebrahim Variava, Yvonne Vaughan-Gordon, Giulio Vecchia, Avy Violari, Richard Vowden, Hylke Waalewijn, Rebecca Wampamba, Steve Welch, Ian Weller, Sibusisiwe Weza, Ellen White, Ian White, Kaja Widuch, Helen Wilkes, Sookpanee Wimonklang, Ben Wynne, Pacharaporn Yingyong, Zaam Zinda Nakawungu, Peter Zuidewind
Journal: The Lancet HIV (2022)

Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg.ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (≥14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127.Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1·4 years (IQR 0·6-2·0) and median weight 8·1 kg (5·4-10·0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112-137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was -10% (95% CI -19% to -2%; p=0·020), demonstrating superiority of dolutegravir. The frequentist estimated difference was -18% (-36% to 2%; p=0·057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1·08 [95% CI 0·47-2·49]; p=0·86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0·93 [0·50-1·74]; p=0·83). No events were considered related to dolutegravir.Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment.Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.